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Hi! David Rosenberg here for the Psychopharmacology Institute. In this CAP—or Child and Adolescent Psychiatry—Smart Take, we will closely examine the role of metformin in treating weight gain associated with second-generation antipsychotic (SGA) treatment in youth. This is a timely report because SGAs are the first-line pharmacotherapy in youth for psychosis, bipolar disorder, treatment-resistant depression, irritability, aggression in autism spectrum disorder and conduct disorders not sufficiently responsive to behavioral interventions, and other off-label conditions. There continues to be a striking increase in SGA prescriptions, with youth being treated with these medicines for extended periods. These medicines are often associated with significant weight gain, which is greater in youth than adults and increases the risk for diabetes and other metabolic disorders. Childhood obesity is already a major public health problem of epidemic proportions, and these children have an increased risk for cardiovascular, metabolic, and behavioral disorders. So, it is critical to identify strategies to combat this epidemic and reduce the risk of SGA-associated weight gain. Of course, diet and exercise are critically important. Whenever I prescribe these agents, I proactively advise patients and their parents how important it is to have an exercise regimen and good diet and nutrition, given the risk of significant weight gain. Exercise and a healthy diet are also associated with enhanced mental health, a win–win strategy.
That being said, despite this, significant weight gain remains a risk in youth treated with SGAs. So, additional treatment strategies are necessary. Metformin is attractive because it is widely used to treat type 2 diabetes and is known to suppress appetite, increase insulin sensitivity, and decrease glucose production and absorption. Studies in adults have found metformin effective and safe in treating antipsychotic-associated weight gain and metabolic abnormalities, but there have been very few studies in children and adolescents. Mansuri and colleagues conducted a comprehensive and systematic review of randomized controlled trials examining the role of metformin in treating weight gain associated with SGA treatment in youth. Moreover, this is the first meta-analysis focused on the safety and effectiveness of metformin for weight gain in youth treated with SGAs.
So, what did they find? Most encouraging was that the randomized controlled trials they examined showed that by only 12–16 weeks after starting metformin treatment, there was a 5-pound reduction in weight compared with placebo. There was also a significant reduction in body mass index (BMI) and insulin resistance. There was even more weight and BMI reduction at 24 weeks of follow-up. Metformin also appeared to help with behavioral symptom relief, as youth treated with metformin had reduced aggression and hostility. There seemed to be an improvement in cholesterol, LDL, HDL, glucose, and insulin levels. However, these were not statistically significant, which may reflect the small sample size and lack of randomized controlled trials in youth. It is also important to note that metformin was associated with significantly more adverse events than placebo, precisely an almost 4-fold higher rate of nausea and vomiting and 3 times higher diarrhea rate than placebo. Most of the side effects seen with metformin were not serious. There was good patient adherence to metformin treatment, and discontinuation rates did not differ significantly between metformin and placebo groups. Most of the side effects were GI side effects, which can be reduced using an extended-release formulation with fewer side effects as well as taking it with a meal and not on an empty stomach. It is also important to note that psychosis itself, independent of SGA use, may contribute to metabolic syndrome.
So, these results are promising, highly clinically relevant, and a good lead, but they are not yet ready for prime time. The overall sample remains small, with only 4 randomized controlled studies in this analysis. The dose and duration of metformin treatment differed across all trials, inclusion criteria for weight gain were different across studies, and in some studies, metformin was used to prevent weight loss. In contrast, others used it as a treatment for weight gain. In 2 of the 4 studies, a fixed dose of metformin was given instead of titrating the dose, which could have led to more side effects or decreased efficacy, as flexible dose titration is what we do in clinical practice to maximize effectiveness and minimize toxicity. The authors correctly note that their findings are encouraging and should be considered promising to lead the way forward for future clinical trials to examine long-term outcomes, determine optimal dosing strategies, impact on psychiatric symptoms, the length of therapy needed, the use of metformin as a preventive and/or treatment strategy, and how to individualize treatment with metformin in patients treated with antipsychotic medication.
Abstract
The Role of Metformin in Treatment of Weight Gain Associated With Atypical Antipsychotic Treatment in Children and Adolescents: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Zeeshan Mansuri, Ramkrishna Makani, Chintan Trivedi, Mahwish Adnan, Ramu Vadukapuram, John Rafael, Ashutosh Lodhi, Abhishek Reddy
Introduction: Second-generation antipsychotics are associated with significant weight gain. The aim of this systematic review and meta-analysis was to determine the efficacy and safety of metformin for the treatment of weight gain in children and young adults treated with second-generation antipsychotics.
Methods: We followed PRISMA guidelines to evaluated studies published before March 2020 in Medline, Google Scholar, PubMed, Cochrane library database, annual scientific sessions of the American Psychiatric Association, American Academy of Child and Adolescent, Psychiatry, and American Society of Clinical Psychopharmacology. Studies included compared metformin with the placebo for management of weight gain in children and adolescents taking atypical antipsychotics. Non-randomized studies, animal experiment studies, editorials, and review studies were excluded. Multiple parameters, including change in anthropometric-biochemical parameters, drug discontinuation rate, and side effects among the groups were assessed. The random-effects method was used for meta-analysis.
Results: Four studies with were included in the final analysis (213 patients; metformin: 106; control: 107). After pooled analysis, 12-16 weeks of metformin therapy was associated with a significant reduction in weight [(mean difference (MD): -4.53 lbs, confidence interval (CI): -6.19 to -2.87, p-value < 0.001)], and BMI z score [MD, -0.09, CI: -0.16, -0.03, p-value: 0.004] compared to control. Metformin was also associated with a significant reduction in insulin resistance [MD: -1.38, CI: -2.26 to -0.51, p-value: 0.002]. There were higher odds of nausea-vomiting [OR: 4.07, CI: 1.32-12.54, p-value: 0.02] and diarrhea [OR: 2.93, CI: 1.50-5.71, p-value: 0.002] in the metformin group. However, there was no difference in drug discontinuation rate [OR: 1.45, CI: 0.41-5.06, p-value: 0.56].
Conclusion: Metformin may prove beneficial in the treatment of weight gain in children treated with second-generation antipsychotics. The pooled treatment effect showed a significant reduction in BMI Z-score and weight in just 12-16 weeks. The limitations include small sample size, variation in metformin dose, and duration of treatment. This meta-analysis should be interpreted as promising, and further larger studies are warranted before drawing a conclusion.
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Reference
Mansuri, Z., Makani, R., Trivedi, C., Adnan, M., Vadukapuram, R., Rafael, J., Lodhi, A., & Reddy, A. (2022).
Frontiers in Psychiatry, 13
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